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CN-113056305-B - Compounds of formula (I)

CN113056305BCN 113056305 BCN113056305 BCN 113056305BCN-113056305-B

Abstract

The present invention relates to compounds of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, Wherein the group X-Y is-NHSO 2 -or-SO 2 NH-;R 1 is H or alkyl, R 2 is selected from COOH and tetrazolyl, R 3 is selected from H, Cl and alkyl, R 4 is selected from H, cl and F, R 5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO 2 -alkyl, cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy, R 6 is H, R 7 is selected from H, CN, haloalkyl, cl, F, SO 2 -alkyl, SO 2 NR 13 R 14 , Optionally substituted heteroaryl and alkyl, R 8 is selected from H, alkyl, haloalkyl and halogen, R 9 is H, C 1 -C 3 alkyl or halogen; R 10 and R 11 together with the nitrogen to which they are attached form an azepanyl group wherein (a) the azepanyl group is substituted with one or more substituents, or (b) one or two carbons in the azepanyl group are selected from O, Or R 10 and R 11 together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl or piperidinyl, wherein (a) the azetidinyl, pyrrolidinyl or piperidinyl is substituted with one or more substituents, or (b) the azetidinyl, One or two carbons of the pyrrolidinyl or piperidinyl group are substituted with a group selected from NH, S and CO, or R 10 and R 11 together with the nitrogen to which they are attached form an 8-, 9-or 10-membered bicyclic heterocycloalkyl group in which one or two carbons of the bicyclic heterocycloalkyl ring are optionally substituted with a group selected from O, NH, S and CO and the bicyclic heterocycloalkyl group is optionally substituted, or R 10 and R 11 together with the nitrogen to which they are attached form a 6-to 12-membered bicyclic group containing a spiro carbon atom in which one or two carbons of the bicyclic group are optionally selected from O, The groups of NH, S and CO are substituted and the bicyclic group is optionally substituted or the bicyclic group is optionally fused with a 5-or 6-membered aryl or heteroaryl, R 13 and R 14 are each independently H or alkyl. Other aspects of the invention relate to the use of such compounds in the field of immunooncology and related applications.

Inventors

  • Martin quebel
  • Anil La Lubai Patel
  • Jason John hills
  • Michael spallenberg
  • Peter Ian Joyce

Assignees

  • 格雷沃尔夫治疗有限公司

Dates

Publication Date
20260505
Application Date
20191122
Priority Date
20181123

Claims (20)

  1. 1. A compound of formula (Id), or a pharmaceutically acceptable salt thereof, Wherein: The group X-Y is-NHSO 2 -or-SO 2 NH-; R 1 is H or C 1-6 alkyl; r 2 is selected from COOH and tetrazolyl; R 3 is selected from H, cl and C 1-6 alkyl; R 4 is selected from H, cl and F; r 5 is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl; R 6 is H; r 7 is CN, SO 2 -C 1-6 alkyl, SO 2 NR 13 R 14 , or heteroaryl selected from imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, and triazolyl, wherein the heteroaryl is optionally substituted with one or more C 1-6 alkyl groups; R 8 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl and halogen; r 9 is H, C 1 -C 3 alkyl or halogen; R 10 and R 11 together with the nitrogen to which they are attached form a 4-, 5-, 6-or 7-membered monocyclic heterocycloalkyl, wherein one or two carbons in the 4-, 5-, 6-or 7-membered monocyclic heterocycloalkyl are optionally substituted with a group selected from O, NH, S and CO, and the 4-, 5-, 6-or 7-membered monocyclic heterocycloalkyl is optionally substituted with one or more groups selected from C 1-6 alkyl, CN, C 3-6 cycloalkyl, OH, C 1-6 alkoxy, halogen and C 1-6 haloalkyl, or R 10 and R 11 together with the nitrogen to which they are attached form an 8-, 9-or 10-membered bicyclic heterocycloalkyl, wherein one carbon in the 8-, 9-or 10-membered bicyclic heterocycloalkyl ring is optionally substituted with a group selected from O and NH and the 8-, 9-or 10-membered bicyclic heterocycloalkyl is optionally substituted with one or more groups selected from C 1-6 alkyl and OH, and R 13 and R 14 are each H.
  2. 2. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 together with the nitrogen to which they are attached form a 6-membered monocyclic heterocycloalkyl, wherein one or two carbons of the 6-membered monocyclic heterocycloalkyl are optionally substituted with a group selected from O, NH, S and CO, and the 6-membered monocyclic heterocycloalkyl is optionally substituted with one or more groups selected from C 1-6 alkyl, CN, C 3-6 cycloalkyl, OH, C 1-6 alkoxy, halogen, C 1-6 haloalkyl.
  3. 3. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 7 is heteroaryl selected from imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, each of which is optionally substituted with one or more C 1-6 alkyl groups.
  4. 4. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 7 is heteroaryl selected from the group consisting of 1H-pyrazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-2-yl, 1H-1,2, 3-triazol-4-yl, 1H-1,2, 3-triazol-5-yl, thiazol-5-yl, 1H-1,2,3, 4-tetrazol-4-yl, 2H-1,2,3, 4-tetrazol-5-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazinyl and 1,3, 4-oxadiazol-2-yl, each of which is optionally substituted with one or more Me groups.
  5. 5. The compound of formula (Id) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (Id) is selected from the group consisting of:
  6. 6. a pharmaceutical composition comprising a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent.
  7. 7. A pharmaceutical composition comprising a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient.
  8. 8. A pharmaceutical composition comprising a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
  9. 9. Use of a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of an ERAP 1-related disorder selected from the group consisting of a proliferative disorder, an immune disorder, a viral disorder and an inflammatory disorder.
  10. 10. The use of claim 9, wherein the disorder is a proliferative disorder.
  11. 11. The use of claim 10, wherein the condition is cancer.
  12. 12. The use of claim 11, wherein the cancer is leukemia.
  13. 13. Use of a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the production of antigen presenting cells presenting neoantigens in vitro or in vivo.
  14. 14. Use of a compound of formula (Id) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for inducing neoantigens in antigen presenting cells.
  15. 15. The use of claim 13 or 14, wherein the antigen presenting cells are dendritic cells.
  16. 16. An immunogenic composition comprising antigen presenting cells obtained or obtainable by the use according to claim 13 or 14, wherein the antigen presenting cells are dendritic cells.
  17. 17. Use of an immunogenic composition according to claim 16 in the manufacture of a pharmaceutical composition for use in treating or preventing cancer in a subject.
  18. 18. The use of claim 17, wherein the immunogenic composition is a vaccine.
  19. 19. The use according to claim 9, wherein the compound is used in combination with immunotherapy.
  20. 20. The use of claim 19, wherein the immunotherapy is an immune checkpoint intervention.

Description

Compounds of formula (I) The present invention relates to compounds capable of modulating ERAP 1. The compounds have potential therapeutic applications in the treatment of a variety of disorders including proliferative disorders, viral disorders, immune disorders, and inflammatory disorders. Background ERAP1 (endoplasmic reticulum aminopeptidase 1; also referred to as APPILS or ARTS 1) is an aminopeptidase which is important 1 in the production of partial antigens and neoantigens (neoantigen) as part of the antigen presentation pathway. The antigen presentation pathway begins with the proteolytic cleavage of a protein into peptides by the proteasome. These peptides are transported to the endoplasmic reticulum where a portion of the peptides are processed by ERAP1 and then bound to the major histocompatibility complex class I (MHC class I) 1. Antigens bound to MHC class I are then transported to the cell surface and presented to CD8 + T cells and recognized as self or non-self substances. Neoantigens are antigens that are specific for cancer and can be recognized by the immune system as foreign, causing destruction of cancer cells. The production of neoantigens is either a direct result of somatic mutations in cancer cell DNA to produce mutant proteins, or an indirect result of somatic mutations in protein processing and expression. The response rate of those cancers with higher mutation rates and correspondingly higher levels of neoantigens to checkpoint inhibitor immunotherapeutic anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-PD-L1 antibodies (e.g., alemtuzumab, avilamab, devaluzumab), and anti-CTLA 4 antibodies (e.g., ipilimumab, tremelimumab) is much higher 2,3 than cancers with lower numbers of neoantigens. The role of ERAP1 in the antigen presentation pathway is to cleave a portion of the peptide by its aminopeptidase activity to produce antigen of optimal length for binding to MHC class I and neoantigen. ERAP1 may also excessively cleave off some neoantigens, thereby preventing them from binding to MHC class I and being presented on the cell surface 4. Removal of ERAP1 activity has been shown to alter antigen and neoantigen antigen libraries, resulting in some antigen/neoantigen presentation and an entirely new antigen/neoantigen presentation enhancement 5. Furthermore, removal of ERAP1 caused CD8 + T cell-dependent tumor rejection 4 in mouse cancer model 4. Thus, modulators of ERAP1 activity, either alone or in combination with current cancer immunotherapeutic agents (including checkpoint inhibitors), are useful in cancer therapy because modulators of ERAP1 activity alter and make more visible to the immune system the antigens and neoantigens presented on the surface of cancer cells, thereby causing the tumor to be attacked and destroyed. It has also been shown that the knockdown of ERAP1 can reduce the level of regulatory-like T cells and enhance natural killer cell killing 6,7 of cancer cells. This suggests that modulators of ERAP1 activity may enable effective cancer treatment by modulating cancer cell visibility and generating a stronger anti-tumor immune response. The peptide treatment of ERAP1 in antigen presentation may also be applied to infectious viral diseases. The present invention seeks to provide compounds capable of modulating ERAP 1. Such compounds have potential therapeutic applications in the treatment of a variety of disorders including proliferative disorders, immune disorders, and inflammatory disorders. Disclosure of Invention The first aspect of the present invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, Wherein: The group X-Y is-NHSO 2 -or-SO 2 NH-; R 1 is H or alkyl; r 2 is selected from COOH and tetrazolyl; R 3 is selected from H, cl and alkyl; R 4 is selected from H, cl and F; R 5 is selected from H, alkyl, haloalkyl, SO 2 -alkyl, cl, alkoxy, OH, CN, alkynyl, alkenyl, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkoxy; R 6 is H; r 7 is selected from H, CN, haloalkyl, cl, F, SO 2 -alkyl, SO 2NR13R14, heteroaryl, and alkyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from alkyl, halogen, alkoxy, CN, haloalkyl, and OH; r 8 is selected from H, alkyl, haloalkyl, and halogen; r 9 is H, C 1-C3 alkyl or halogen; R 10 and R 11 together with the nitrogen to which they are attached form an azepanyl group, wherein (a) the azepanyl group is substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein the heteroaryl is in turn optionally further substituted with one or more groups selected from halogen and alkyl, or (b) one or two carbons in the azepanyl group are replaced with groups selected from O, NH, S and CO, and the azepanyl group is optionally substituted with one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halogen, haloalkyl and heteroaryl, wherein